title: Complexation with beta-cyclodextrin confers oral activity on the flavonoid dioclein.
abstract: Dioclein is a flavonoid reported to have many beneficial effects on the cardiovascular system such as vasorelaxant, hypotensive, antioxidant and antiarrythmogenic activities. However, use as pharmaceuticals is limited due to the lack of oral activity and low water solubility. In this work, intending to improve its oral activity, we performed a 1:1 inclusion complex (IC) between dioclein and beta-cyclodextrin (beta-CD). The IC was characterized by nuclear magnetic resonance and infrared spectroscopy and its vasodilator and hypotensive effects were evaluated in mice. The inclusion of dioclein in beta-CD increased the water solubility 44% compared to free dioclein. The IC (2.5mgkg(-1)) produced a higher and long lasting change in systolic blood pressure (SBP) after intraperitoneal administration compared to free dioclein. When given orally, free dioclein (10mgkg(-1)) showed no hypotensive effect while the IC induced a pronounced decrease in SBP. The in vitro vasodilator effect of dioclein was unchanged by its inclusion in beta-CD showing that the IC does not change the interaction between dioclein and its cellular targets. In conclusion, our results show that the new complex prepared by inclusion of dioclein in beta-CD improves the hypotensive effect of the flavonoid by increasing its bioavailability and enables dioclein to be effective after oral administration. The mechanism underling the increase in bioavailability is probably a consequence of a protective effect of beta-CD against in vivo biodegradation by enzymes and possibly increased water solubility.
authors.affiliation: Departamento de Fisiologia e Biofísica, ICB, Universidade Federal de Minas Gerais, Av Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Rezende
authors.forename: Steyner F
authors.initials: SF
authors.lastname: Cortes
authors.forename: Frederico B
authors.initials: FB
authors.lastname: De Sousa
authors.forename: Ivana S
authors.initials: IS
authors.lastname: Lula
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.forename: Rubén D
authors.initials: RD
authors.lastname: Sinisterra
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Lemos
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000737:chemistry*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D044950:Flavanones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D051379:Mice; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000277:Adjuvants, Pharmaceutic; D044950:Flavanones; D014665:Vasodilator Agents; D047392:beta-Cyclodextrins; C094747:dioclein; C031215:betadex